title: PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation.
abstract: IKKbeta serves as a central intermediate signaling molecule in the activation of the NF-kappaB pathway. However, the precise mechanism for the termination of IKKbeta activity is still not fully understood. Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, PPM1A and PPM1B, as IKKbeta phosphatases. Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation. PPM1A and PPM1B associate with the phosphorylated form of IKKbeta, and the interaction between PPM1A/PPM1B and IKKbeta is induced by TNFalpha in a transient fashion in the cells. Furthermore, knockdown of PPM1A and PPM1B expression enhances TNFalpha-induced IKKbeta phosphorylation, NF-kappaB nuclear translocation and NF-kappaB-dependent gene expression. These data suggest that PPM1A and PPM1B play an important role in the termination of TNFalpha-mediated NF-kappaB activation through dephosphorylating and inactivating IKKbeta.
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, United States.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Sun
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Tan
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
authors.forename: Amy K
authors.initials: AK
authors.lastname: Pass
authors.forename: Meijin
authors.initials: M
authors.lastname: Chu
authors.forename: Dekai
authors.initials: D
authors.lastname: Zhang
authors.forename: Xiongbin
authors.initials: X
authors.lastname: Lu
authors.forename: Songbin
authors.initials: S
authors.lastname: Fu
authors.forename: Xia
authors.initials: X
authors.lastname: Lin
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000378:metabolism; D008163:Luminescent Measurements; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; C000607456:PPM1A protein, human; C000607457:PPM1B protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C